Effects of exercise after oesophagectomy on body composition and adequacy of energy and protein intake: PERFECT multicentre randomized controlled trial

Julius Center for Health Sciences and Primary Care, University Medical Center Utrecht, Utrecht University, Utrecht, The Netherlands Department of Dietetics, University Medical Center Utrecht, Utrecht, The Netherlands Department of Radiation Oncology, University Medical Center Utrecht, Utrecht, The Netherlands Department of Surgery, University Medical Center Utrecht, Utrecht, The Netherlands Department of Surgery, Catharina Hospital, Eindhoven, The Netherlands Department of Surgery, ZGT Hospital, Almelo, The Netherlands Department of Surgery, IJsselland Hospital, Capelle a/d IJssel, The Netherlands Department of Surgery, Amsterdam UMC location VUmc, Amsterdam, The Netherlands Department of Surgery, Radboud University Medical Center, Nijmegen, The Netherlands Department of Surgery, Erasmus Medical Center, Rotterdam, The Netherlands Department of Surgery, Amsterdam UMC location University of Amsterdam, Amsterdam, The Netherlands Cancer Center Amsterdam, Cancer Treatment and Quality of Life, Amsterdam, The Netherlands Department of Medical Oncology, Amsterdam UMC location University of Amsterdam, Amsterdam, The Netherlands Department of Gastroenterology and Hepatology, Radboud University Medical Center, Nijmegen, The Netherlands


Introduction
Patients with localized oesophageal cancer may experience long-lasting symptoms following cancer treatment (that is often neoadjuvant chemo(radio)therapy followed by oesophagectomy) 1,2 , resulting in suboptimal intake of nutrients in the first postoperative year 3 . This might cause persistent weight and muscle loss and a progressive decline in nutritional status [4][5][6][7][8][9] . Strategies to counteract weight and muscle loss involve exercise and nutritional interventions 10,11 . However, specific recommendations for nutritional interventions during oncological exercise programmes are lacking 12 .
In the randomized Physical ExeRcise Following Oesophageal Cancer Treatment (PERFECT) study, a 12-week supervised exercise programme was demonstrated to be safe and feasible after oesophagectomy and effective in terms of improved quality of life (QoL) (primary outcome), role functioning, and cardiorespiratory fitness 13 . As part of the secondary analysis of the PERFECT study, the aim is to assess whether or not participants in the PERFECT study meet their energy and protein requirements and investigate exercise effects on body composition, malnutrition risk, and energy expenditure. Getting more insight into this would be of great importance for optimal nutritional strategies during the recovery phase.

Setting and participants
The PERFECT study is a multicentre randomized controlled trial performed in nine Dutch hospitals between 2015 and 2019. The design of the PERFECT study has been published previously 14 . The trial was registered on 19 January 2015 in the Dutch Trial Register (NTR 5045) (https://trialsearch.who.int/Trial2.aspx? TrialID = NTR5045). See Text S1 for inclusion and exclusion criteria. The study was approved by the Medical Ethics Committee of the University Medical Center (UMC) Utrecht and the local Ethical Boards of participating hospitals.
After signing written informed consent and completing baseline measurements, participants were randomly allocated to a 12-week supervised exercise intervention (EX) or usual care group (UC).

Dietetic study
Patients included in the UMC Utrecht were asked to participate in optional dietetics measurements. During these measurements, resting energy expenditure (REE), body composition, and nutritional status were measured.
Additional informed consent was obtained before baseline testing and randomization.

Intervention
The exercise intervention consisted of a 12-week supervised, individualized, combined aerobic and resistance exercise programme, in addition to UC. Details of the exercise programme have been published elsewhere and are summarized in Text S1 14 . Table 1 provides an overview of all outcome measures of the PERFECT study, which are of interest for the current secondary analysis. Detailed information about all outcome measures can be found in Text S1.

Statistical analysis
A paired samples t test was performed to assess adequacy of dietary intake. All outcomes were analysed as between-group differences in outcomes using intention-to-treat analysis of covariance (ANCOVA). Detailed information can be found in Text S1.

Participants
In total, 79 of all 120 PERFECT participants were invited to participate in the optional dietetic measurements and 37 participants agreed. In the dietetic study, five participants were lost to follow-up (EX: three of 19, UC: two of 18) (Fig. S1).
Baseline and nutritional characteristics of all PERFECT participants and participants in the dietetic study are shown in Table S1 and Table S2 respectively.

Dietary intake
At baseline (3 (2-7) months postoesophagectomy (median, interquartile range (i.q.r.)), participants had a mean energy and protein intake of 2413 kcal/day (s.d. = 640) and 94 gram/day (s.d. = 28) respectively. No clinically relevant changes in energy and protein intake were observed in either group during the intervention period. Postintervention, energy and protein intake were comparable between groups ( Table 2). At baseline, 63.2 per cent and 37.6 per cent of all participants had an adequate energy and protein intake respectively (Tables S3-S5). At 12 weeks these percentages were 66.0 per cent and 33.3 per cent respectively.

Weight and risk for malnutrition
EX had a non-significant lower weight at 12 weeks compared with UC (−1.19 kg, 95 per cent c.i. −2.48 to 0.10, ES = 0.09) ( Table 2). Malnutrition risk declined within EX, but no significant difference was observed when compared with UC.

Dietary intake
Postintervention, no significant differences in energy and protein intake between EX and UC were observed ( Table 2). EX had a lower protein intake per kg weight per day (−0.11 g per kg per day, 95 per cent c.i. −0.23 to 0.01) and per kg fat free mass (FFM) per day (−0.18 g per kg FFM per day, 95 per cent c.i. -0.33 to −0.02) post-intervention compared with baseline. Similarly, a decline in adequacy of protein intake in g/FFM was observed from baseline to 12 weeks in EX (from 57.9 per cent to 25.0 per cent) ( Tables S5 and S6). An adequate energy intake at baseline and 12 weeks respectively, was found in 52.6 per cent and 43.8 per cent of EX and 58.8 per cent and 43.8 per cent of UC (Table S4).

Weight and body composition
Postintervention, the between-group difference in weight was −1.51 kg (95 per cent c.i. −4.56 to 1.54, ES = 0.12). This decline in weight was mainly due to a decreased fat mass (FM) index from baseline to 12 weeks in EX (−0.51, 95 per cent c.i. −0.94 to −0.09), whereas the FFM index remained stable over time ( Table 2) Table 2).  Table 2).

Discussion
This study showed that the majority of patients after oesophagectomy do not meet estimated protein requirements, especially when increasing physical activity levels as part of an exercise programme. Only slightly more than half of all participants meet the estimated energy requirements. These numbers were even lower when energy intake was compared with daily energy requirements calculated using the mREE. Measurement of REE is recommended to personalize energy needs 15 . Patients participating in the PERFECT exercise programme were observed to lose more weight compared with controls, which seemed to be mainly loss of FM. FFM, which is commonly used as a proxy for skeletal muscle mass, remained stable over time in the exercise group. Since the exercise programme included progressive resistance training, an increase in muscle mass was expected. This counterintuitive finding could potentially be explained by the decreased protein intake in the exercise group. These findings suggest the need for a structured nutritional intervention, in addition to an exercise programme, which likely will result in larger effects of the exercise programme 16,17 . This might be of even greater importance for patients receiving immunotherapy after surgery in order to be able to complete this treatment 18 .
Exercise had a positive effect on the risk of being malnourished, while energy and protein intake was inadequate and patients participating in the exercise programme lost weight. The questionnaire used to measure risk of malnutrition consists of four domains: weight, food intake, nutrition impact symptoms, and activities and function. The scores for these particular domains remained fairly stable over time and were not different between groups, except for the nutrition impact symptom domain (Table S2). This suggests that the PERFECT exercise programme reduces patients' relevant symptoms, leading to improvements in the patients' nutritional status 13 .
This study has several limitations. Only half of the PERFECT participants decided to participate in the dietetic study, hampering the generalizability of the findings. Secondary outcomes are reported here, for which the study was not powered. Due to self-selection, patients who participated in the dietetic study had a relatively higher risk of malnutrition at Table 2 Effects of the PERFECT exercise intervention on weight, risk for malnutrition and dietary intake among all participants in the PERFECT study (n = 120) and effects of the PERFECT exercise intervention on weight, body composition, nutritional status, resting energy expenditure, and dietary intake in the dietetic subgroup (n = 37)

Baseline
Baseline to 12 weeks (post-intervention) baseline (43.2 per cent) compared with all participants (32.5 per cent). Finally, no data were available regarding the number of consultations with a dietitian during the study period and the specific recommendations that were given during this encounter. The present study shows that patients in the first year after oesophagectomy are at risk of a suboptimal energy and protein intake, especially when increasing physical activity levels as part of an exercise programme. The results suggest that exercise has a small positive effect on the risk of being malnourished, and weight loss was mainly loss of FM and not FFM. These findings highlight the need for specific nutritional recommendations during oncological exercise programmes.

Funding
The PERFECT study was funded by the World Cancer Research Fund The Netherlands (WCRF NL, project number 2013/997). They had no role in the study design, collection, analysis or interpretation of the data, writing the manuscript, or the decision to submit the paper for publication.